Skin malignancies include skin cancers and cutaneous metastases. Skin cancers form in the tissues of the skin. There are several types of skin cancers which include melanoma (malignant melanoma), basal cell carcinoma, squamous cell carcinoma, neuroendocrine carcinoma of the skin, Merkel cell tumors, dermatofibrosarcoma protruberans, and Kaposi's sarcoma. The major types of skin cancers include melanoma, basal cell carcinoma, and squamous cell carcinoma. Melanoma is a skin cancer that forms in melanocytes (skin cells that make pigments). Basal cell carcinoma forms in the lower part of the epidermis and squamous cell carcinoma forms in squamous cells. Neuroendocrine carcinoma of the skin forms in neuroendocrine cells. The vast majority of skin cancers are basal cell carcinomas and squamous cell carcinomas, and they generally do not spread to other parts of the body (metastasize). Melanomas tend to spread to other parts of the body. Kaposi's sarcoma is a relatively rare type of skin malignancy that afflicts the elderly or those with an abnormal immune system such as those with AIDS. Kaposi's sarcoma is a lesion (tumor) of the skin characterized by soft purplish plaques and papules that form nodules on the skin.
A cutaneous (skin) metastasis refers to a growth of cancer cells in the skin originating from an internal cancer or a skin cancer such as melanoma. A cutaneous metastasis occurs when cancerous cells break away from the primary cancer tumor and travel to the skin typically through the blood circulation or lymphatic system. Cutaneous metastases have been reported as manifestations of the following cancers: breast, lung, nasal sinus, larynx, oral cavity, colorectal, stomach, ovary, testis, bladder, prostate, cervical, vaginal, thyroid, endometrial, kidney, esophagus, pancreas, liver, melanoma and Kaposi's sarcoma (including AIDS-related Kaposi's sarcoma). Cutaneous metastases are increasingly prevalent and occur in approximately 10% of patients with metastatic cancer (Lookingbill et. al., Cutaneous metastases in patients with metastatic carcinoma: A retrospective study of 4020 patients, J Am Acad Dermatol 29:228-236, 1993). Women with skin metastases have the following distribution in decreasing order of frequency of primary malignancies: breast, ovary, oral cavity, lung, and large intestine. In men, the distribution is as follows: lung, large intestine, oral cavity, kidney, breast, esophagus, pancreas, stomach, and liver. (Alcaraz et al., Cutaneous Metastases from Internal Malignancies: A Clinicopathologic and Immunohistochemical Review, Am J Dermatopathol 34:347-393, 2012). With advances in cancer treatment, patients are living longer and thus, are more likely to develop cutaneous metastases.
Generally, a cutaneous metastasis lesion is a firm, round or oval mobile, non-painful nodule or nodules with intact overlying epidermis. Sometimes nodules develop ulceration and secondary infection. Other signs of a skin metastasis can be the presence of plaques, papules, or red patches. Cutaneous metastases can cause pain, infection, bleeding and/or disfigurement, and can negatively impact the quality of life of the patient.
The incidence of cutaneous metastases in patients with breast carcinoma was recently reported as 23.9% (Lookingbill et. al.). Cutaneous metastases from breast carcinoma are the most common metastases observed by dermatologists (De Giorgi et. al., Cutaneous manifestations of breast carcinoma, Dermatol Therapy, 23:581-589, 2010). These cutaneous metastases most commonly occur on the chest wall and abdomen, but may also occur at the extremities and on the head and neck region. Nodules are the most common form of these cutaneous metastases. They range in size from 1 to 3 cm and are firm solitary or multiple lesions in the dermis or subcutaneous tissue.
Various treatments for skin cancer and cutaneous metastases are available including systemic therapy and skin-directed therapy. However, systemic therapy has limited efficacy with respect to treatment of cutaneous metastases (Spratt et al., Efficacy of Skin-Directed Therapy for Cutaneous Metastases from Advanced Cancer: A Meta-Analysis, J Clin Oncol, 32:3144-3155, 2014).
Skin-directed therapy includes electrochemotherapy (ECT), photodynamic therapy (PDT), radiotherapy (RT), intralesional therapy (ILT), and topical therapy. ECT, PDT, RT, and ILT all require administration by a medical practitioner or technician, whereas topical therapy can be administered by the patient. Thus, topical therapy can be less costly than other therapies and can also allow for greater patient compliance since the therapy can be administered by the patient at home. However, topical therapy that included compositions of imiquimod or miltefosine for the treatment of cutaneous metastases had low response rates and only showed improved response rates when combined with other skin-directed therapies (Spratt et. al.). In a meta-analysis of 47 prospective studies of 4,313 cutaneous metastases, the objective response rate to the aforementioned therapies (including radiotherapy) was 60.2% (Spratt et al.). ECT demonstrated the best response rate (complete response rate 47.5%); however, ECT is an inpatient procedure requiring general anesthesia and often results in notable pain and dermatologic toxicity (inflammation, hyperpigmentation, and ulceration) (Cabula et al., Electrochemotherapy in the Treatment of Cutaneous Metastases from Breast Cancer: A Multicenter Cohort Analysis, Ann Surg Oncol (2015) 22:S442-S450). The less invasive alternatives, such as intralesional therapy and topical therapy demonstrate reduced efficacy in comparison to ECT. When effective reduction of cutaneous metastases cannot be achieved, as is often the case, healthcare providers must fall back on palliative wound care remedies (Fernandez-Anton Martinez, et al., Metástasis cutáneas de origen visceral, Actas Dermosifiliogr. 2013; 104(10):841-853). Thus, the availability of topical therapeutic compositions that are efficacious in treating cutaneous metastases without the need to combine the therapy with other skin-directed therapies would be beneficial. There is therefore a significant unmet need for an effective, less invasive alternative therapy for cutaneous metastases in patients already struggling with significant morbidity from the symptoms of and treatments for advanced primary cancer.
Delivery of therapeutic drugs into viable epidermis and dermis of the skin can be a challenge due to the barrier properties of the stratum corneum, the outermost layer of the epidermis. The delivery of poorly water soluble drugs into the skin can be even more of a challenge. Skin penetration enhancers have been employed in topical drug formulations to increase the penetration of drugs into the skin and have had some success. However, some penetration enhancers such as solvents and surfactants can be irritating to the skin. Volatile silicone fluids have been employed in topical formulations to increase the penetration of drugs into the skin; however, high concentrations of volatile silicone fluids, i.e., 25% and greater, and/or combinations of volatile silicone fluids with other potential skin irritating compounds such as alcohols, e.g., C1 to C4 aliphatic alcohols, surfactants, other penetration enhancers, and other volatile solvents have been needed to produce the penetration enhancement effect. Additionally, some penetration enhancers will cause the drug to penetrate transdermally and be systemically absorbed, which is not desirable when only treating a condition of the skin (e.g., epidermis and/or dermis). Other topical delivery systems have been employed where the drug is chemically modified with surfactants and other substances, but these materials can also be irritating to the skin.
Taxanes, including paclitaxel and docetaxel, have been used for the treatment of cancer for many years. These compounds are typically characterized as being poorly water soluble. The cancer treatment formulation initially developed for intravenous (IV) infusion injection, TAXOL® (BMS), is paclitaxel dissolved in a 50:50 v/v mixture of polyethoxylated castor oil (CREMOPHOR® EL) and dehydrated ethanol. However, the systemic use of this formulation results in significant clinical toxicity (Rowinsky et al. 1993). Substantial effort has been devoted to the development of CREMOPHOR EL-free formulations of paclitaxel (Ma and Mumper, 2013). One such formulation is disclosed in U.S. Pat. No. 8,221,779, herein incorporated by reference, which discloses injectable aqueous compositions of antimitotic drug microparticles, including paclitaxel, useful for the treatment of cancers by intraperitoneal and intravenous (IV) injection of the compositions.
Topical treatment of skin cancers currently includes topical formulations of 5-fluorouracil (5-FU), imiquimod, and ingenol mebutate. However, the use of these formulations can cause local skin irritation such as burning, redness, dryness, pain, swelling, itching, tenderness, and ulceration at the site of application.
Currently, there are no FDA approved topical taxane formulations for the treatment of skin cancer or cutaneous metastases in the U.S. Previous topical therapy treatments of cutaneous metastases using compositions containing other active ingredients may have been ineffective in part, because of the inability of the composition to penetrate into the skin to the affected tissue.